All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
The prevalence of obesity in the United States, and worldwide is increasing. Approximately 35 percent of U.S. adults 20 or older are overweight (i.e., have a body mass index [BMI] of 25 to 29.9), and an additional 30 percent are obese (i.e., have a BMI that is greater than or equal to 30). Among children, an estimated 16 percent of children ages 6-11 are overweight, over twice as many as two decades ago. Among adolescents ages 12-19, the percentage of obesity has more than tripled from 5 to 16 percent. Although extreme obesity has received the most attention in the clinical setting, moderate obesity is more common in the general population. However, even moderate obesity can contribute to chronic metabolic abnormalities characteristic of the insulin resistance syndrome, such as dyslipidemia, hypertension, insulin resistance, and glucose intolerance particularly when it is associated with intra-abdominal fat deposition (i.e. central obesity). Although it is likely that no single factor is responsible for the increased prevalence of moderate obesity, it is likely that environmental elements are interacting with predisposing genetic factors, and identification of the acquired causes contributing to an increase in the prevalence of obesity is key to developing public health policy and dietary and physical activity recommendations. Existing research indicates that weight, physical activity, and nutrition alter cancer risk and carcinogenesis for many cancers, and evidence is accumulating on the effect of these health factors on cancer prognosis and quality of life among cancer survivors. A recent study of a very large prospective cohort of 900,000 U.S. adults estimated that overweight and obesity in the US could account for 14 percent of all deaths from cancer in men and 20 percent of those in women. An International Agency Research on Cancer (IARC) review entitled, “Weight Control and Physical Activity”, summarized the evidence across basic and population research, and estimated that between one-quarter and one-third of the cases of many common cancers may be attributable to the combined effect of increased body weight and inadequate physical activity.
The role of dietary changes as contributing factors to the development of obesity are under investigation, and along with an increase in total energy consumption over the past few decades, a clear shift in the types of nutrients consumed in the American diet has been highlighted. Specifically, the consumption of fructose has increased dramatically, primarily because of increased consumption of beverages that are high in fructose and the consumption of other foods such as breakfast cereals, baked goods, condiments, and prepared desserts sweetened with sucrose and high-fructose corn syrup (HFCS). HFCS is produced by the enzymatic isomerization of dextrose to fructose, and most HFCS used in beverages contains about 55% fructose. Its commercial use increased in the 1970s so that by 1985, HFCS accounted for about 35% of the total amount of sweeteners by dry weight in the food supply. Intakes based on the 1977-1978 US Department of Agriculture Nationwide Food Consumption Survey estimated the mean individual consumption of fructose in adolescents and adults was about 40 g/d, the range being 29-54 g/d. Thirteen of the 40 g of dietary fructose was estimated to come from naturally occurring sources of fructose, and 27 g from added sources of fructose. More recent data on fructose consumption in the United States are not available, but food disappearance data, which can serve as an indicator of trends in consumption over time show that although the per capita use of sucrose has decreased moderately from 46.4 kg (102 lb) in 1970 to 30.5 kg (67 lb) in 1997, the per capita use of HFCS has increased from a negligible 0.23 kg (0.5 lb) in 1970 to 28.4 kg (62.4 lb) in 1997. This means that the combined consumption of sucrose, and high fructose corn syrup have increased by 26% from 64 g/day in 1970 to 81 g/day in 1997. This represents an average daily energy intake from added fructose of about 1356 kJ (324 kcal). In fact, just two 355-mL (12-oz) soft drinks can supply up to 50 g/fructose (about 840 kJ, or 200 kcal) or >10% of the daily energy requirements for an average-weight woman, without considering any other dietary sources of fructose. Thus, fructose consumption now makes up a significant proportion of energy intake in the American diet, and this increase in fructose consumption has coincided with the increased prevalence of obesity over the past 2 decades. These observations raise the question as to whether current fructose intakes could contribute to weight gain and its metabolic sequelae, including cancer.
Pancreatic cancer is the fourth leading cause of death in the US (Czito B. Willett C. Clark J. et al: Chemoradiation for unresectable pancreatic cancer. in Cameron J L (ed). Pancreatic Cancer. Hamilton. Ontario. Canada. B C Decker. 2001), 5-year survival is only 5%. Present molecular pathology, and cancer genetic studies indicate that pancreatic adenocarcinoma originates from pancreatic ductal cells, arises via a series of progressive structural stages of neoplastic growth, termed pancreatic intraepithelial neoplasia (PanINs), that are precursors to pancreatic adenocarcinomas, and associated with genetic alterations occurring in a temporal sequence (Bardeesy N, DePinho R A. Pancreatic Cancer Biology, and genetics Nat Rev Cancer 2: 897-909, 2002; Cubila A L, Fitzgerald P J. Morphological lesions associated with human primary invasive nonendocrine pancreas cancer. Cancer Res 36, 2690-9, 1976). The earliest abnormalities include activating KRAS mutations, detectable in ˜30% of the earliest PanIN (Kinstra D S, Longnecker D S. K-ras mutations in pancreatic ductal proliferative lesions. Am J pathol 145, 1547-50, 1994; Rozenblum E et al. Tumor-suppressive pathways in pancreatic cancer. Cancer Res 57, 1731-4, 1997), and altered epidermal growth factor (EGF) signaling (both ERBB2 or Her2/neu, and ERBB3) (Korc M et al. Overexpression of the epidermal growth factor receptor in human pancreatic cancer is associated with concomitant increases in the levels of epidermal growth factor and transforming growth factor alpha. J Clin Invest 90, 1352-60 1992; Friess H et al. Pancreatic cancer: the potential clinical relevance of growth factors and their receptors. J Mol Med 74; 35-42 1996; Siblia M et al. The EGF receptor provides an essential survival signal for SOS-dependent skin tumor development. Cell 102, 211-220 2000). In late stage PanINs, inactivation of INK4A (Rozenblum E et al. Tumor-suppressive pathways in pancreatic cancer. Cancer Res 57, 1731-4, 1997), and TP53 (Rozenblum E et al. Tumor-suppressive pathways in pancreatic cancer. Cancer Res 57, 1731-4, 1997) are observed, the former cooperatively accentuating RAS oncogenicity (Chin L et al. Cooperative effects of INK4A, and RAS in melanoma susceptibility in vivo. Genes Dev 11, 2822-2834 1997), and the latter facilitating genetic instability, including telomere dysfunction (Chin L et al. P53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell 97 527-538 1999). Inherited BRCA2 mutations, typically associated with familial breast, and ovarian tumors are found in ˜17% of late stage pancreatic cancers in families harboring BRCA2 mutations (Cancer risks in BRCA2 mutation carriers. The breast cancer linkage consortium. J Natl Cancer Inst 91; 1310-1316 1999; Goggins M, Hruban R H, Kern S E. BRCA2 is inactivated in the development of pancreatic intraepithelial neoplasia: evidence and implications. Am J Pathol 156; 1767-1771, 2000), and late PanINs frequently manifest loss of SMAD/DPC4, which encodes a key transcriptional regulator of transforming growth factors-γ family signaling (Hahn S A et al. DPC4, a candidate tumor suppressor gene at human chromosome 19q21.1. Science 271 350-353 1996; Luttges J et al. Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol 158 1677-1683 2001).
The only well-established environmental etiologic factor is cigarette smoking, although chronic pancreatitis has been reported to confer a 20-fold excess risk (Lowenfels A B, Maisonneuve P, Cavallini G, et al., Pancreatitic and the risk of pancreatic cancer. N Engl J Med 1993; 328: 1433-7), and evidence points to an association between diabetes mellitus and pancreas cancer, but whether these diseases are due to a common exposure or are causally connected remains unknown (Anderson K E, Potter J D, Mack T M. Pancreatic cancer. In: Schottenfeld D, Fraumeni J Jr, eds. Cancer epidemiology and prevention. New York, N.Y.: Oxford University Press, 1996: 725-71; Everhart J, Wright D. Diabetes mellitus as a risk factor for pancreatic cancer: a meta-analysis. JAMA 1995; 273: 1605-9). Additionally, higher fasting plasma glucose (>140 mg/dl) (Jee S H, Ohrr H, Sull J W, Yun J E, Samet J M. Fasting serum glucose level and cancer risk in Korean men and women. JAMA 2005; 293: 194-202), or postload (Gapstur S M, Gann P H, Lowe W, et al. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 2000; 283: 2552-8) plasma glucose levels have been associated with increased pancreas cancer mortality. A number of studies have investigated the role of dietary factors in pancreatic cancer risk. As with other epithelial cancers, a diet high in vegetables and fruit—and perhaps specifically high in folate has been associated with a lower risk, though not consistently (World Cancer Research Fund Panel. Food, nutrition, and the prevention of cancer a global perspective. Washington, D.C.: American Institute for Cancer Research, 1997; Nkondjock A, Krewski D, Johnson K C, Ghadirian P, and the Canadian Cancer Registries Epidemiology Research Group. Dietary patterns and risk of pancreatic cancer. Int J Cancer May 1; 114(5):817-823, 2005.). Other studies have identified dietary intake of lycopene or vitamin C as potentially protective factors (Nkondjock A, Ghadirian P, Johnson K C, Krewski D and the Canadian Cancer Registries Epidemiology Research Group. Dietary intake of lycopene is associated with reduced pancreatic cancer risk. J Nutr 135:592-597, 2004; Lin Y, Tamakoska A, Hayakawa T, Narus S, Kitagawa M and Ohno Y. Nutritional factors and risk of pancreatic cancer: A population-based case-control study based on direct interview in Japan. J Gastroenterol. March 40(3):324-325, 2005). Some studies have reported increased pancreatic cancer risk associated with high cholesterol intake (Lin Y, Tamakoska A, Hayakawa T, Narus S, Kitagawa M and Ohno Y. Nutritional factors and risk of pancreatic cancer: A population-based case-control study based on direct interview in Japan. J Gastroenterol. March 40(3):324-325, 2005), and at least six case control studies have reported a positive association between meat intake, and pancreatic cancer risk (Gapstur S M, Gann P H, Lowe W, et al. Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 2000; 283: 2552-8; Howe G R and Burch J D. Nutrition and pancreatic cancer. Cancer Causes Control 7:69-82, 1996). However, in the large prospective 18-year follow-up Nurse Health Study of 121,700 women, no relationship between total fat, fat type, and cholesterol was observed in the 178 women who developed pancreatic cancer (Michaud D S, Giovannucci E, Willett W C, Colditz G A and Fuchs C S. Dietary meat, dairy products, fat and cholesterol and pancreatic cancer risk in a prospective study. J Epidemiol 157(12):1115-1125, 2003).